CN105481757A - Preparation method of pimavanserin - Google Patents

Preparation method of pimavanserin Download PDF

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Publication number
CN105481757A
CN105481757A CN201510982141.2A CN201510982141A CN105481757A CN 105481757 A CN105481757 A CN 105481757A CN 201510982141 A CN201510982141 A CN 201510982141A CN 105481757 A CN105481757 A CN 105481757A
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Prior art keywords
reaction
preparation
yield
binding agent
transformation efficiency
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Chinese (zh)
Inventor
程刚
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BEIJING KANG LISHENG PHARMACEUTICAL TECHNOLOGY DEVELOPMENT Co Ltd
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BEIJING KANG LISHENG PHARMACEUTICAL TECHNOLOGY DEVELOPMENT Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

The invention relates to a preparation method of pimavanserin. The preparation method takes 4-fluorobenzylamine as a raw material and comprises the following steps: performing reductive amination on the 4-fluorobenzylamine and N-methyl-4-piperidone; performing butt joint on the product and benzyl chloroformate; finally, reacting with 4-isobutoxybenzylamine to prepare the pimavanserin. The preparation method provided by the invention is simple, convenient and feasible, has high yield and good quality and is convenient for industrial production.

Description

The preparation method of a kind of piperazine Ma Selin
Technical field:
The present invention relates to medicinal chemistry art, be specifically related to the preparation method of a kind of piperazine Ma Selin.
Background technology
Formerly grind the patent CN01806126.5 (applying date: 2001.03.06, authorize) document such as patent families: CN200710136949.4 (CN01806126.5 divisional application), WO0166521 (2001.09.13) describes the synthetic method of a kind of piperazine Ma Selin, and its synthetic route is as follows:
The deficiency of this route is to have employed isocyanic acid 4-butoxy benzyl ester, and the less and less stable in its market, is not suitable for suitability for industrialized production.
Route two:
Formerly grind the patent CN200480004479.0 (applying date: 2004.01.15, authorize) patent families: CN200880016491.1 (2008.03.19), CN201010546028.7 (CN200480004479.0 divisional application), CN200910225582.2 (CN200480004479.0 divisional application, authorize), the document such as US2008/280886, WO2004/808, US2009/82342 describes the synthetic method of a kind of piperazine Ma Selin, its synthetic route is as follows:
This route steps is longer, and the preparation drafting intermediate isocyanic acid 4-butoxy benzyl ester needs the phosgene using toxicity larger, is not suitable for suitability for industrialized production.
Technical scheme
For above-mentioned document weak point, the present invention redesigns its synthetic route, with with 4-flunamine for starting raw material, first with N-methyl-4-piperidone reduction amination, then dock with chloroformic acid benzyl ester, react with 4-isobutoxy benzylamine under the effect of triethylamine, prepare piperazine Ma Selin, this preparation method is simple and easy to do, yield is high, and quality is good, be convenient to suitability for industrialized production, synthetic route is as follows:
The Optimization analyses process of the first step reaction:
The selection of catalyst type:
The selection of the first step reduction amination catalyzer is respectively sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride catalyzer, and compare, result is as shown in table 1.
The selection of the catalyzer of table 1 the first step reduction reaction
Catalyzer Reaction conditions Transformation efficiency
Sodium borohydride 25℃，12h 100％
Sodium triacetoxy borohydride 25℃，12h 90％
Sodium cyanoborohydride 25℃，12h 85％
As can be seen from Table 1, when sodium cyanoborohydride is as catalyzer, reaction conversion ratio is minimum; When sodium triacetoxy borohydride is as catalyzer, reduction amination transformation efficiency makes moderate progress.Reforming sodium borohydride rate is best.
The investigation of catalyzer usage quantity
Table 2NaBH 4the reaction conditions of catalyzer compares
As can be seen from Table 2,2.0eqNaBH 4, 1.5eqNaBH 4with 1.0eqNaBH 4during as catalyzer, transformation efficiency and the basic indifference of yield, consider that the many aftertreatments of catalyzer usage quantity are complicated, in sum, and 1.0eqNaBH 4as catalyzer, experiment condition is better.
The Optimization analyses process of second step reaction conditions:
The selection of acid binding agent kind:
The selection of second step substitution reaction acid binding agent is respectively pyridine, triethylamine, quadrol acid binding agent, and compare, result is as shown in table 3.
The selection of the acid binding agent of table 3 second step substitution reaction
Acid binding agent Reaction conditions Transformation efficiency
Pyridine 25℃，3h 97％
Triethylamine 25℃，3h 90％
Quadrol 25℃，3h 80％
As can be seen from Table 3, when quadrol is as acid binding agent, reaction conversion ratio is minimum; When triethylamine is as acid binding agent, reaction conversion ratio is lower; When adopting pyridine as acid binding agent, transformation efficiency and yield are all higher, in sum, adopt pyridine to be optimum operational condition as acid binding agent.
The investigation of acid binding agent usage quantity
The reaction conditions of table 4 pyridine acid binding agent compares
As can be seen from Table 4, when 110% pyridine and 150% pyridine are as acid binding agent, transformation efficiency and the basic indifference of yield; When 90% pyridine is as acid binding agent, not only the reaction times needs to extend, and transformation efficiency is lower, and in sum, 110% pyridine is as acid binding agent, and experiment condition is better.
The Optimization analyses process of three-step reaction condition:
The selection of temperature of reaction:
Three-step reaction temperature is respectively 25 DEG C, 40 DEG C, 65 DEG C, compares, and result is as shown in table 5.
The selection of table 5 three-step reaction temperature
Temperature of reaction Reaction times Transformation efficiency Yield
25℃ 25h 75％ 60％
40℃ 10h 95％ 90％
65℃ 8h 99％ 80％
As can be seen from Table 5, when temperature of reaction is 25 DEG C, transformation efficiency and yield are very low; When temperature of reaction is 40 DEG C, transformation efficiency and yield higher; When temperature of reaction is 65 DEG C, transformation efficiency is very high, but yield is very low.In sum, when temperature of reaction is 40 DEG C, experiment condition is better.
The selection in reaction times:
Table 6 reaction times condition compares
Temperature of reaction Reaction conditions Transformation efficiency Yield
40℃ 5h 70％ 75％
40℃ 10h 95％ 90％
40℃ 20h 96％ 91％
As can be seen from Table 6, temperature of reaction is at 40 DEG C, and the reaction times is 10h and 20h transformation efficiency and the basic indifference of yield; Reaction times is that 5h transformation efficiency and yield are very low.In sum, when the reaction times is 10h, experiment condition is better.
The investigation of refining solvent
Table 7 refining solvent condition compares
Refining solvent Upgrading result Yield
Crude product It is 0.54% that maximum list is mixed, product purity 98.2% -
Methyl alcohol It is 0.31% that maximum list is mixed, product purity 98.5% 72％
Acetonitrile It is 0.17% that maximum list is mixed, product purity 98.2% 82％
Virahol It is 0.04% that maximum list is mixed, product purity 99.8% 89％
Ethyl acetate It is 0.25% that maximum list is mixed, product purity 98.2% 85％
As can be seen from Table 7, when methyl alcohol, acetonitrile and ethyl acetate are as refining solvent, refining effect is poor, all has the impurity being greater than 0.1%, when adopting Virahol as refining solvent, refining effect is better, all impurity is all less than 0.1%, and yield is higher, in sum, adopt Virahol as refining solvent, experiment condition is better.
The synthesis of embodiment 1:4-(4-fluorobenzylamino)-1-methyl piperidine
4-flunamine (125.0g) and N-methyl-4-piperidone (113.0g) is added in anhydrous methanol (1300ml), stirring at room temperature, after 1 hour, is cooled to 0 DEG C, adds sodium borohydride (57.0g) in batches, slowly rise to 25 DEG C, reaction 12h.In reaction solution, add 1000ml water, then use ethyl acetate (500ml) to extract 2 times, anhydrous sodium sulfate drying, decompression steams solvent, obtains 182.0g title compound.(yield is 81.9%).
1H-NMR(500MHz，d 6-DMSO)：1.46-1.47(2H，m)，1.70-1.72(2H，m)，2.18-2.20(2H，m)2.26(3H，s)，2.28-2.30(2H，m)，3.80-3.82(2H，s)，6.84-6.86(2H，m)，7.03-7.05(2H，m)。
HPLC：98.7％。
The analysis condition of HPLC:
High performance liquid chromatograph is equipped with UV-detector
Chromatographic column: common C18 post
Determined wavelength: 242nm
Column temperature: 30 DEG C
Sample size: 10 μ l
Moving phase: for mobile phase A, acetonitrile is Mobile phase B, and according to the form below carries out wash-out with 0.025mol/L potassium dihydrogen phosphate (regulating pH value to 6.0 with triethylamine).
-flow velocity is per minute 1.0ml
Time (minute) Mobile phase A (%) Mobile phase B (%)
0 60 40
20 35 65
30 35 65
31 65 35
35 65 35
The synthesis of embodiment 2:4-(4-fluorine benzyloxycarbonyl amino)-1-methyl piperidine
To N, 4-(4-fluorobenzylamino)-1-methyl piperidine (100.0g) is added and pyridine (71.1g) is cooled to 10 DEG C in dinethylformamide (1000ml), slowly add chloroformic acid benzyl ester (115.5g), be warming up to 25 DEG C of reaction 3h.Poured into by reaction solution in water (2000ml), stir 30 minutes, filter, drying obtains 142.7g title compound.(yield is 89.0%).
1H-NMR(500MHz，d 6-DMSO)：1.58-1.60(2H，m)，1.84-1.86(2H，m)2.18-2.20(2H，m)，2.28(3H，s)2.28-2.30(2H，m)，3.59-3.61(1H，m)，4.23(2H，s)，5.34(2H，s)，6.83-6.85(2H，d，J＝4.5Hz)，7.03-7.05(2H，d，J＝5.0Hz)，7.19(5H，m)。
HPLC：99.0％。
The analysis condition of HPLC:
-high performance liquid chromatograph is equipped with UV-detector
-chromatographic column: common C18 post
-determined wavelength: 242nm
-column temperature: 30 DEG C
-sample size: 10 μ l
-moving phase: for mobile phase A, acetonitrile is Mobile phase B, and according to the form below carries out wash-out with 0.025mol/L potassium dihydrogen phosphate (regulating pH value to 6.0 with triethylamine).
-flow velocity is per minute 1.0ml
-
Time (minute) Mobile phase A (%) Mobile phase B (%)
0 60 40
20 35 65
30 35 65
31 65 35
35 65 35
Embodiment 3: the synthesis of piperazine Ma Selin
To N, add 4-(4-fluorine benzyloxycarbonyl amino)-1-methyl piperidine (50.0g), 4-isobutoxy benzylamine (27.6g) and triethylamine (28.3g) in dinethylformamide (500ml), 40 DEG C are stirred 10h.Poured into by reaction solution in water (1000ml), stir 30 minutes, filter, recrystallisation from isopropanol, obtains 43.2g title compound.(yield is 71.8%).
1H-NMR(d 6-DMSO)：1.00-1.02(6H，d，J＝7.8Hz)，1.65-1.72(4H，m)，2.18-2.22(4H，m)2.26(3H，s)，2.33-2.35(1H，m)，3.58-3.61(1H，m)，3.89-3.91(2H，d，J＝6.8Hz)，4.41(2H，s)，4.41(2H，s)，6.64-6.66(1H，d，J＝4.5Hz)，6.64-6.66(1H，d，J＝4.5Hz)，6.86-6.88(1H，d，J＝5.5Hz)，6.86-6.88(1H，d，J＝5.5Hz)，6.94-6.96(1H，d，J＝5.0Hz)，6.94-6.96(1H，d，J＝5.0Hz)，7.04-7.06(1H，d，J＝3.5Hz)，7.04-7.06(1H，d，J＝3.5Hz)，10.34(1H，s)。
HPLC：99.5％。
The analysis condition of HPLC:
High performance liquid chromatograph is equipped with UV-detector
Chromatographic column: common C18 post
Determined wavelength: 242nm
Column temperature: 30 DEG C
Sample size: 10 μ l
Moving phase: for mobile phase A, acetonitrile is Mobile phase B, and according to the form below carries out wash-out with 0.025mol/L potassium dihydrogen phosphate (regulating pH value to 6.0 with triethylamine).
Flow velocity is per minute 1.0ml
Time (minute) Mobile phase A (%) Mobile phase B (%)
0 60 40
20 35 65
30 35 65
31 65 35
35 65 35

Claims (1)

1. a preparation method of piperazine Ma Selin, is characterized in that: with 4-flunamine for starting raw material, first with N-methyl-4-piperidone reduction amination, then docks with chloroformic acid benzyl ester, and last and 4-isobutoxy benzylamine reacts, and prepares piperazine Ma Selin.
CN201510982141.2A 2015-12-25 2015-12-25 Preparation method of pimavanserin Pending CN105481757A (en)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105820110A (en) * 2016-05-09 2016-08-03 杭州科巢生物科技有限公司 Novel synthesis method for pimavanserin
CN106179449A (en) * 2016-07-18 2016-12-07 南京工业大学 The Co catalysts of a kind of carbon-nitrogen material load and the method for synthesis piperazine Ma Selin intermediate
WO2017015272A1 (en) * 2015-07-20 2017-01-26 Acadia Pharmaceuticals Inc. Methods for preparing n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form c
US10449185B2 (en) 2017-08-30 2019-10-22 Acadia Pharmaceuticals Inc. Formulations of pimavanserin
CN110483431A (en) * 2019-09-04 2019-11-22 桂林南药股份有限公司 Linezolid impurity compound, preparation method and its application
US10517860B2 (en) 2016-03-25 2019-12-31 Acadia Pharmaceuticals Inc. Combination of pimavanserin and cytochrome P450 modulators
US10953000B2 (en) 2016-03-25 2021-03-23 Acadia Pharmaceuticals Inc. Combination of pimavanserin and cytochrome P450 modulators
US11135211B2 (en) 2017-04-28 2021-10-05 Acadia Pharmaceuticals Inc. Pimavanserin for treating impulse control disorder
US11345693B2 (en) 2017-08-21 2022-05-31 Acadia Pharmaceuticals Inc. Compounds, salts thereof and methods for treatment of diseases
US11440884B2 (en) * 2017-08-21 2022-09-13 Acadia Pharmaceuticals Inc. Compounds, salts thereof and methods for treatment of diseases
US11464768B2 (en) 2016-12-20 2022-10-11 Acadia Pharmaceuticals Inc. Pimavanserin alone or in combination for use in the treatment of Alzheimer's disease psychosis

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US11840515B2 (en) 2015-07-20 2023-12-12 Acadia Pharmaceuticals Inc. Methods for preparing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form c
WO2017015272A1 (en) * 2015-07-20 2017-01-26 Acadia Pharmaceuticals Inc. Methods for preparing n-(4-fluorobenzyl)-n-(1-methylpiperidin-4-yl)-n'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form c
US10981870B2 (en) 2015-07-20 2021-04-20 Acadia Pharmaceuticals Inc. Methods for preparing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form
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US10517860B2 (en) 2016-03-25 2019-12-31 Acadia Pharmaceuticals Inc. Combination of pimavanserin and cytochrome P450 modulators
US10953000B2 (en) 2016-03-25 2021-03-23 Acadia Pharmaceuticals Inc. Combination of pimavanserin and cytochrome P450 modulators
US11191757B2 (en) 2016-03-25 2021-12-07 Acadia Pharmaceuticals Inc. Combination of pimavanserin and cytochrome P450 modulators
CN105820110A (en) * 2016-05-09 2016-08-03 杭州科巢生物科技有限公司 Novel synthesis method for pimavanserin
CN105820110B (en) * 2016-05-09 2018-07-24 杭州科巢生物科技有限公司 Mo Fanselin synthetic methods
CN106179449A (en) * 2016-07-18 2016-12-07 南京工业大学 The Co catalysts of a kind of carbon-nitrogen material load and the method for synthesis piperazine Ma Selin intermediate
CN106179449B (en) * 2016-07-18 2018-11-13 南京工业大学 A kind of Co catalysts that carbon-nitrogen material loads and the method for synthesizing piperazine Ma Selin intermediates
US11464768B2 (en) 2016-12-20 2022-10-11 Acadia Pharmaceuticals Inc. Pimavanserin alone or in combination for use in the treatment of Alzheimer's disease psychosis
US11135211B2 (en) 2017-04-28 2021-10-05 Acadia Pharmaceuticals Inc. Pimavanserin for treating impulse control disorder
US11440884B2 (en) * 2017-08-21 2022-09-13 Acadia Pharmaceuticals Inc. Compounds, salts thereof and methods for treatment of diseases
US11345693B2 (en) 2017-08-21 2022-05-31 Acadia Pharmaceuticals Inc. Compounds, salts thereof and methods for treatment of diseases
US10449185B2 (en) 2017-08-30 2019-10-22 Acadia Pharmaceuticals Inc. Formulations of pimavanserin
US10849891B2 (en) 2017-08-30 2020-12-01 Acadia Pharmaceuticals Inc. Formulations of pimavanserin
US11452721B2 (en) 2017-08-30 2022-09-27 Acadia Pharmaceuticals Inc. Formulations of pimavanserin
US10646480B2 (en) 2017-08-30 2020-05-12 Acadia Pharmaceuticals Inc. Formulations of pimavanserin
CN110483431A (en) * 2019-09-04 2019-11-22 桂林南药股份有限公司 Linezolid impurity compound, preparation method and its application

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Application publication date: 20160413